Pyrazolones containing wholly or



Patented Jan. 26, 1937 UNITED STATES FATENT OFFICE PYRAZOLONESCONTAINING WHOLLY OR PARTIALLY HYD R GENATED CYCLIC the-Main- Hochst,

Germany,

assignors to Winthrop Chemical Company, Inc., New York, N. Y., acorporation of New York No Drawing. Application January 31,

Serial No. 709,232. 1933 l Claims.

As is known, the 1-ary1-2-alky1-5-pyrazolones or their derivatives beingsubstituted in 4-posi'- tion by amino. groups show febrifuge andsedative properties.

Now we have found that when in the process usual for obtaining5-pyrazo1ones and their 4-amino-derivatives, there are used parentmaterials, intermediate products or adjuvants which contain at least atone nitrogen atom a partially or wholly hydrogenated cyclic hydrocarbonradical, or allow of the introduction of such a radical at nitrogenatoms, there are obtained S-pyrazolones and 4-amino-derivatives thereof,which contain at least at one nitrogen atom a parls tially or whollyhydrogenated cyclic hydrocarbon radical and are distinguished by a goodfebrifuge and sedative action. The products have the following generalformula:

tially hydrogenated cyclic hydrocarbon radical, R2 for alkyl or a whollyor partially hydrogenated cyclic hydrocarbon radical, R3 for alkyl, andR4 for hydrogen, alkyl or the group wherein X1 and X2 stand forhydrogen, alkyl, aralkyl, or a wholly or partially hydrogenated cyclichydrocarbon radical, at least one wholly or partially hydrogenatedcyclic hydrocarbon radical being present in the molecule.

When starting from the hydrazines, the process may, for instance, followthe known methods for producing 5-pyrazolones and 4-amino-derivativesthereof. If, for example, cyclohexylhydrazine is condensed withacetoacetic ester there is obtained the1-cyclohexyl-3-methyl-5-pyrazolone which is transformed by methylationinto the 1-cyclohexy1-2.3-dimethyl5-pyrazolone. When starting fromsymmetrically disubstituted hydrazines, there are directly obtained inone operation, by condensation with acetoacetic ester the 5-pyrazo1onestrisubstituted in 1-2-3-position.

1934, In Germany February 8,

Thus, by condensing symmetrical dicyclohexylhydrazine with acetoaceticester there is obtained the l.2-dicyclohexyl-3-methyl-5-pyrazo1one orfrom symmetrical cyclohexyl-cyclohexenylhydrazine thecyclohexyl-cyclohexenyl-3-methyl-5- pyrazolone. The same or similarpyrazolone derivatives may be obtained when starting from the monoorsymmetrically disubstituted hydrazines by condensation with, forinstance, unsaturated acids, such as crotonic acid or esters thereof,oxidation of the pyrazolidones obtained and, if desired, subsequentalkylation of the products containing no substituent in the Z-position.

Furthermore the new compounds may be obtained by introducing into thepyrazolones obtainable according to the process of this invention anamino group which contains as substituent or substituents at least onealkyl group or a Wholly or partially hydrogenated cyclic hydro- H carbonradical or both. By treating, for instance, the1-cyclohexyl-2.3-dimethyl-5-pyrazolone 0btainable according to thepresent invention with nitrous acid and methylating the reductionprodnot of the resultant nitroso compound, the 1-cyc1ohexyl-2.3-dimethyl-4- dimethylamino- 5 -pyrazolone is obtained.Finally, the process may also be carried out by introducing into knownpyrazolone derivatives, for instance, into1-phenyl-2.3-dimethy1-4-amino-5-pyrazolone, a wholly or partiallyhydrogenated cyclic hydrocarbon radical. Thus, from1-pheny1-2.3-dimethyl-4- methylamino-ii-pyrazolone there is obtainedwith bromocyclohexene the 1-phenyl-2.3-dimethyl-4-methylcyclohexenylamino-5-pyrazolone.

The compounds of this invention, in so far as they contain a hydrogenatom capable of being exchanged may be rendered soluble in water byintroduction of suitable groups, such as by conversion intoaldehydebisulfites or sulfoxylates.

The following examples illustrate the invention, the parts being byweight unless otherwise stated:

(1) parts of cyclo-hexylhydrazine and parts of acetoacetic ester aremixed, while cooling; the mixture is heated for half an hour on a steambath and is then dissolved in acetic ester;

on cooling the solution the 1-cyclohexyl-3- methyl-B-pyrazolonecrystallizes; it melts at 152 C. By methylating the product with methyliodide at 120 C. or with dimethylsulfate at 170 C. there is obtained thel-cyclohexyl-2.3-dimethyl-S-pyrazolone which is recrystallized fromacetic ester and then melts at 66 C. It is very readily soluble in waterand organic solvents.

33 parts of 1-cyclohexyl-2.3-dimethyl-5-pyrazolone are dissolved in asmall portion of water; the solution is mixed with 100 parts by volumeof 2N-hydrochloric acid, and to the mixture cooled to 0 C. 100 parts byvolume of 2N-sodium nitrite solution are added, drop by drop. The green4-nitroso-compound is thus precipitated; it is filtered by suction andconverted by the action of the usual reducing agents, such as zinc dustin hydrochloric acid solution or catalytically activated hydrogen, intothe 4-amino compound; the latter is recrystallized from acetic ester andthen melts at 104 C.; it is readily soluble in water and alcohol. Withthe aid of methylating agents, such as formaldehyde and formic acid,there is obtained from it the 1-cyclohexyl-2.3- dimethyl 4dimethylamino-5-pyrazolone. The latter is recrystallized from benzine orhexahydrobenzene and then melts at 77 C.; it is readily soluble in waterand alcohol and sparingly soluble in cold benzine and coldhexahydrobenzene.

By causing 2 molecular proportions of l-cyclohexyl-2.3-dimethyl-4-amino5-pyrazolone to react in a benzene solution with 1 molecular proportionof bromocyclohexene, eliminating the precipitated hydrobromide ofl-cyclohexyl-2.3- dimethyl-4-amino-5-pyrazolone by filtration anddistilling the benzene, thel-cyclohexyl-ZB-dimethyl-4-cyclohexenylamino-5-pyrazolone is obtained.

Instead of the methyl groups there may be introduced into the 4-aminogroup one or two benzyl groups, cyclohexyl groups or hexyl groups, and,for instance, one benzyl group and one methyl group or one cyclohexylgroup and one methyl group. At the 2-nitrogen atom there may be attachedinstead of the methyl group also another alkyl group or ethyl orisopropyl. When starting from a'higher homologue of acetoacetic ester,pyrazolones are obtained which contain a substituent in 'B-position, forinstance, ethyl or propyl.

The compound monomethylated in 4-position is obtainable from1-cyclohexyl-2.3dimethyl-4- amino-5-pyrazolone by adding dimethylsulfateto the 4-benzylidene-compound and splitting off benzaldehyde. It melts,after redissolution from a mixture of hexahydrobenzene and benzine, at102 C. and shows solubilities similar to those of the dimethyl compound.

(2) 100 parts of symmetrical dicyclohexylhydrazine and 70 parts ofacetoacetic ester are heated for 6 hours to a temperature between 160 C.and 180 C. After cooling, the whole is mixed with acetic ester andalcoholic hydrochloric acid until there is a strongly acid reaction toCongo paper; the hydrochloride of 1.2-dicyclohexyl-3-methyl-S-pyrazolone is thus precipitated. The free base isrecrystallized from benzine and then melts at 85 C.; it is sparinglysoluble in water and readily soluble in alcohol. By treatment withnitrous acid and reduction 'in a manner analogous to that described inExample 1, the compound is converted into the 1.2-dicyclohexyl-3-methyl-4amino-5-pyrazolone, the hydrochloride of which melts, afterrecrystallization from alcohol containing hydrochloric acid, at 205 C.

20 parts of 1.2-dicyclohexyl-3-methy1-4-amino 5-pyrazolone hydrochlorideare heated for 3 hours on a steam bath with formaldehyde and formicacid. After cooling, the base is separated by addition of alkali and isdissolved in ether; the ethereal residue is mixed with acetic ester andan excess of alcoholic hydrochloric acid. The hydrochloride of1.2-dicyclohexyl-3-methyl- 4-dimethylamino-5-pyrazolone crystallizes; itis recrystallized from alcohol containing hydrochloric acid and thenmelts at 206 C. The free base melts at 83 C., when recrystallized frompetroleum ether; it is sparinglysoluble in water and readily soluble inalcohol. In this case, too, the groups mentioned in Example 1 may beintroduced in like manner into the 4-amino group and into the3-position.

From the 1.2-dicyclohexyl-3methyl-4-amino- 5-pyrazolone there isobtained, in a manner analogous to that described in Example 1, the 1.2-dicyclohexyl-3-methyl-4-methylamino-5-pyrazolone, and by reaction withformaldehyde-bisulfite, its water solubleformaldehydebisulfite-compound.

(3) 203 parts of 1-phenyl-2.3-dimethyl-4-amino-5-pyrazolone aredissolved in about ten times their weight of benzene; to this solutionthere are added 80.5 parts of l-bromocyclohexene-2.3 of the formula:

H CH JJH! CHBr and the mixture is boiled on a steam bath until theseparation of salt which soon sets in has ceased. After cooling the saltis eliminated by filtering with suction; the benzene solution is shakenwith dilute hydrochloric acid and the hydrochloric acid solution is madealkaline by means of potassium carbonate. The 1-phenyl-2.3dimethyll-cyclohexenylamino-5-pyrazo1one which first separates in theform of an oil soon solidifies. When recrystallized from alcohol andhexahydrobenzene it forms compact crystals which melt at 93 C. The newcompound is readily soluble in most of the organic solvents, with theexception of petroleum ether. It is sparingly soluble in water andreadily soluble in dilute mineral acids.

(4) In the same manner as described in Example 3 there is obtained from217 parts of 1-phenyl 2.3-dimethyl-4-methylamino 5 pyrazolone and 80.5parts of bromocyclohexene the 1-phenyl-2.3- dimethyll-(methylcyclohexenyl) -amino 5 pyrazolone, which when recrystallized fromdilute alcohol, melts at 84 C. to 86 C. It shows about the samesolubility as the compound described in Example 3.

(5) The 1-phenyl-2.3-dimethyl-4 -dicyclohexenylamino-5-pyrazolone isprepared in a manner analogous to that described in Example 3 from 283parts of 1-phenyl-2.B-dimethyll-cyclohexenylamino-S-pyrazolone and 80.5parts of bromocyclohexene. When recrystallized from dilute alcohol, itmelts at 94 C. to 95 C. It is sparingly soluble in water and readilysoluble in most of the organic solvents.

In the same manner as described in Examples 3, 4 and 5 there may beintroduced into the 4- amino group cyclohexyl and cyclohexadienylradicals or both radicals simultaneously.

(6) Equimolecular quantities of sodium acetate and cyclopentylhydrazinehydrochloride (melting point 130 C.) are well stirred at 80 C. for 2hours in ten times their weight of water with the calculated quantity ofacetoacetic ester. The 1- cyclopentyl-3-methyl-5 pyrazolone obtained isfiltered with suction; when recrystallized from alcohol it melts at 139C. By methylating it with methyl iodide at C. or with dimethylsulfate at170 C. the 1-cyclopentyl-2.3-dimethyl-5-pyrazolone is obtained whichboils under 3 mm. pressure at 161 C. to 163 C.

36 parts of l-cyclopentyl-Z.3-dimethyl-5-pyrazolone are dissolved in asmall portion of water; 120 parts by volume of 2N-hydrochloric acid areadded; the solution is cooled to 0 C. and 100 parts by volume of2N-sodium nitrite solution are gradually added thereto, drop by drop.The green 4-nitroso-compound is filtered with suction and converted withthe aid of the usual reducing agents into thel-cyclopentyl-Z.3-dimethyl-4-amino-5-pyrazolone, which boils under 4 mm.pressure at 178 C. to 182 C. and, when recrystallized from a mixture ofacetic ester and hexahydrobenzene, melts at 63 C. By the action ofmethylating agents, such as formaldehyde and formic acid, there isobtained from the 4-amino-compound the 1-cyclopentyl-2.3-dimethyl-4dimethylamino 5- pyrazolone which boils under 3 mm. pressure at C. Theradicals mentioned in Example 1 may be introduced into the 4-amino groupor into the 2- or 3-position.

(7) 28 parts of methylacetoacetic ester and 22 parts ofcyclohexylhydrazine are heated together for one hour on a steam bath.100 parts of acetic ester are then added and the mixture is allowed tocool. The 1-cyclohexyl3.4-dimethy1-5-pyrazolone crystallizes. 19 partsthereof are heated for 8 hours at 170 C. with 13 parts ofdimethylsulfate. After cooling, the whole is mixed with water andcaustic potash solution and shaken with benzene; distillation followsafter drying and distilling the benzene in a vacuum. Thel-cyclohexyl-2.3.4-trimethyl-5-pyrazolone obtained boils under 4 mm.pressure at 163 C. to C. It is readily soluble in water and the usualorganic solvents.

(8) 32 parts of 1-cycl0hexy1-3-methyl-5-pyrazolone (obtained accordingto Example 1) are dissolved in 150 parts of alcohol and hydrogenated at80 C. in the presence of 3 parts of a nickel catalyst and 20 parts ofacetone under a hydrogen pressure of 40 atmospheres. When the absorptionof hydrogen is complete, the alcohol is distilled; the residue isdissolved in a small amount of acetic ester; the solution is allowed tocool and the 1-cyclohexyl-3-methyl-4- isopropyl-5-pyrazolone which hasseparated is filtered by suction. It melts at 102 C. and is sparinglysoluble in water. 22 parts of the 4-isopropyl compound obtained areheated for 8 hours at C. with 13 parts of dimethylsulfate. After workingup according to Example '7 thel-cyclohexyl-2.3-dimethyl-4-isopropy1-5-pyrazolone is obtained whichboils under 4 mm. pressure at 165 C. to 170 C. It solidifies on somestanding; when recrystallized from benzine it melts at 7 3 C.

We claim:

1. The compounds of the following general formula:

R4-C=C-R$ wherein R1 stands for phenyl or a wholly or partiallyhydrogenated 5- or 6-membered cyclic hydrocarbon radical, R2 for alkylor a wholly or partially hydrogenated 5- or 6-membered cyclichydrocarbon radical, R3 for alkyl, and R4 for hydrogen, alkyl or thegroup mo 0: N-CH:

s C CH In H,

said compound being colorless, readily soluble in water and alcohol andhaving a feebly alkaline reaction.

3. The compound of the following formula:

said compound being colorless and of a feebly alkaline reaction.

4. The compound of the following formula:

said compound being colorless and of a feebly alkaline reaction.

MAX BocKMiiHL. WALTER KROHS.

